Modified release dosage forms

ABSTRACT

A dosage form comprises: (a) at least one active ingredient: (b) a core having a first surface portion upon which resides a first coating and a second surface portion which is substantially free of the first coating; and (c) a shell which resides upon at least a portion of the second surface portion, wherein the shell comprises a different material from the first coating. In another embodiment, the dosage form comprises: (a) at least one active ingredient; (b) a core comprising a center portion having an exterior surface and an annular portion having an exterior surface and an interior surface, wherein the annular portion interior surface is in contact with at least a portion of the center portion exterior surface, and a coating resides on at least a portion of the annular portion exterior surface; and (c) a shell which resides upon at least a portion of the exterior surface of the center portion, wherein the shell comprises a different material than the impermeable coating. In another embodiment, the dosage form comprises: (a) at least one active ingredient; (b) a core having an outer surface and a cavity which extends at least partially through the core such that the core outer surface has at least a first opening therein; (c) a first coating which resides on at least a portion of the core outer surface, wherein the first shell portion comprises a different material from the first coating; and (d) a first shell portion which is adjacent to the first opening and covers at least the first opening.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to modified release dosage forms such as modifiedrelease pharmaceutical compositions. More particularly, this inventionrelates to modified release dosage forms having partial coatings, forexample dosage forms partially coated by first material for controllingthe surface area through which dissolution of at least one activeingredient contained within the dosage form takes place upon contactingof the dosage form with a liquid medium.

2. Background Information

Modified release pharmaceutical dosage forms have long been used tooptimize drug delivery and enhance patient compliance, especially byreducing the number of doses of medicine the patient must take in a day.For this purpose, it is often desirable to modify the rate of release ofdrug (one preferred type of active ingredient) from a dosage form intothe gastrointestinal (g.i.) fluids of a patient, especially to slow therelease to provide prolonged action of the drug in the body. In manycases, it is particularly desirable to provide a constant (i.e.zero-order) release rate of the drug. For patients taking a particularmedication on a chronic basis, matching the rate of drug absorption intothe circulatory system with its rate of metabolism and excretion fromthe body could enable achievement of a steady state in which arelatively constant level of drug is maintained in the blood. This canhave the advantageous effect of minimizing undesirable side effectswhich may occur at high blood levels, while maintaining a therapeuticlevel of the active ingredient (e.g. drug) in the body.

The rate at which an orally delivered pharmaceutical active ingredientreaches its site of action in the body depends on a number of factors,including the rate and extent of drug absorption through the g.i.mucosa. To be absorbed into the circulatory system (blood), the drugmust first be dissolved in the g.i. fluids. For many drugs, diffusionacross the g.i. membranes is relatively rapid compared to dissolution.In these cases, the dissolution of the active ingredient is the ratelimiting step in drug absorption, and controlling the rate ofdissolution allows the formulator to control the rate of drug absorptioninto the circulatory system of a patient.

The dissolution rate of a drug in the g.i. fluids depends, among otherthings, on the drug's solubility and the effective surface area ofcontact between dissolving drug particles and the dissolution medium.The Nernst-Brunner equation describes the dissolution rate of a drug:dC/dt=(D K ₂ S) (1/vh) (C _(s) −C _(t))where dC/dt is the drug dissolution rate, D is the diffusion coefficientfor the drug, K is a dissolution constant, h is the effective thicknessof the diffusion layer, S is the surface area of contact between thedrug and the dissolution medium, C_(s) is the solubility of the drug inthe medium (i.e. the concentration of a saturated solution at thesurface of the dissolving particle), and C_(t) is the concentration ofdrug in the bulk solution at a time t. In the body, the absorptionprocess constantly removes drug from the g.i. tract, usually at a ratefaster than that of drug dissolution. This creates what is known as a“sink” condition, where C_(s), the concentration of drug in the bulksolution, is much less than C_(s), the concentration of drug in thesaturated region at the surface of the dissolving particle.

The primary non-constant terms in this model are S, the surface area ofcontact between the drug and the dissolution medium, and h, theeffective thickness of the diffusion layer. In a typical sustainedrelease matrix tablet, the surface area of contact between the drug anddissolution medium decreases over time, while in a diffusional matrixsystem, the path-length for diffusion increases over time, as thedissolution “front” recedes from the surface towards the center of thedosage form. The combination of these effects results in a decrease indissolution rate of the drug over time.

Various dosage forms have been proposed to approach a constantdissolution rate by employing dosage form shapes in which the surfacearea of contact between the drug and dissolution medium increase at thesame rate as the path-length for diffusion. Most involve coating aportion of the dosage form with an impermeable layer to control thesurface area available for dissolution of the drug. See for example,U.S. Pat. Nos. 3,146,169; 3,851,638; 4,663,147; 4,816,262; and6,110,500. One shape of particular interest has been that of a torus.Another has been that of a truncated cone. The primary limitation ofsuch designs has been laborious manufacturing processes which typicallyinclude making a core, coating the core with impermeable material, thenremoving a portion of the core and coating to create the area for drugdissolution. These types of processes have not been shown to be suitablefor commercial scale manufacture.

U.S. Pat. No. 4,803,076 discloses a tablet press for use in themanufacture of a tablet in the approximate shape of a truncated cone, aswell as an apparatus for removal of a portion of the coated dosage formin order to expose an area for dissolution of the drug. However, thedosage form disclosed therein suffers from the limitation of possessinga flat cylinder or disc shaped central portion, defined by the straightdie walls, and a “land” area defined by the perimeter of the upper andlower punches in the compression machine.

There remains an unmet need for a commercially efficient method ofproducing a partial coating on a dosage form. Such partial coatingswould be useful for controlling the surface area through which drug isreleased from the dosage form, including providing a surface area fordrug release from the dosage form that remains constant during the drugrelease period; and providing a surface area for drug release from thedosage form that increases during the drug release period. The apparatusand methods described in copending U.S. patent application Ser. No.09/966,497, pages 27-51 and Ser. No. 09/966,450, pages 57-63, thedisclosures of which are incorporated herein by reference,advantageously enable manufacture of partially coated dosage formswithout the need for a partial coating removal step.

It would additionally be desirable to have a method for making suchpartially coated dosage forms with a further shell portion, residingupon at least a portion of the uncoated core surface, for example todeliver an immediate release loading dose of one or more activeingredients; or to confer a unique elegant appearance. It would beparticularly desirable for the shell portion to reside upon and coveronly the uncoated portion of the core surface, and not the first coatingmaterial. In would further be desirable to make the shell portionoptionally removable by the consumer or healthcare professional prior toingestion of the dosage form in order to customize dosing. Anotherbeneficial use for such partially coated dosage forms include ascontainers for holding liquid or solid materials, which may be removedfrom the dosage form for example by removing the shell portion, andpouring through the uncoated portion prior to use. It would additionallybe desirable to have a modified release dosage form comprising aninactive core having a specialized shape or structure, and comprisingfor example swelling or gelling excipients, which effect the release ofactive ingredient from one or more shell compartments.

It would also be desirable to coat non-conventionally shaped dosageforms that provide constant controlled release rates by virtue of theirshape with a shell of a more regular shape to facilitate swallowing, orreduce friability (susceptibility to breakage). For example it would beuseful to have dosage forms comprising a core in the shape of a torus ortruncated cone containing an active ingredient therein, protected by aspheroid or elypsoid shaped shell. Such dosage forms would be easy toswallow, maintain their structural integrity during handling andshipping, and yet provide the functional benefits conferred by the shapeof the core. The apparatus and methods of copending U.S. patentapplication Ser. No. 09/966,497, pages 27-51 and Ser. No. 09/966,450,pages 57-63 advantageously enable the production of such dosage formsaccording to this invention.

It is one object of this invention to provide a dosage form in which atleast one active ingredient contained therein exhibits a modifiedrelease profile upon contacting of the dosage form with a liquid medium.It is another object of this invention to provide a dosage form in whichthe surface area for dissolution of at least one active ingredientcontained therein is controlled by a partial coating. Other objectsfeatures and advantages of the invention will be apparent to thoseskilled in the art from the detailed description set forth below.

SUMMARY OF THE INVENTION

In one embodiment, the dosage form of this invention comprises: (a) atleast one active ingredient; (b) a core having a first surface portionupon which resides an first coating and a second surface portion whichis substantially free of the first coating; and (c) a shell whichresides upon at least the second surface portion, wherein the shellcomprises a different material from the first coating.

In another embodiment, the core comprises a cavity therein such that atleast part of the second surface portion of the core is located withinthe cavity, and the shell resides upon at least a part of the secondsurface portion of the core which is located within the cavity.

In another embodiment, the cavity is an aperture which extends entirelythrough the core such that the aperture provides the second surfaceportion of the core.

In another embodiment, the shell resides upon at least part of both thefirst coating and the second surface portion of the core.

In another embodiment, the shell resides over all the first coating andthe second surface of the core.

In another embodiment, the shell comprises a material selected fromwater soluble or water swellable thermoplastic film formers, watersoluble or water swellable thickeners, crystallizable andnon-crystallizable carbohydrates.

In another embodiment, the core is in the shape of a truncated cone.

In another embodiment, the dosage form of this invention comprises: (a)at least one active ingredient; (b) a core comprising (i) a centerportion having an exterior surface and (ii) an annular portion having anexterior surface and an interior surface, wherein the annular portioninterior surface is in contact with at least portion of the centerportion exterior surface, and an first coating resides on at least aportion of the annular portion exterior surface; and (c) a shell whichresides upon at least a portion of the exterior surface of the centerportion, wherein the shell comprises a different material from the firstcoating.

In another embodiment, the core comprises at least one activeingredient.

In another embodiment, the center portion of the core comprises at leastone active ingredient.

In another embodiment, the annular portion of the core comprises atleast one active ingredient.

In another embodiment, the center portion of the core comprises a firstactive ingredient and the annular portion of the core comprises a secondactive ingredient.

In another embodiment, the shell comprises at least one activeingredient.

In another embodiment, both the shell and the core each comprise atleast one active ingredient.

In another embodiment, the first coating resides upon the entire annularportion exterior surface.

In another embodiment, the shell resides upon the entire first coatingand the center portion surface.

In another embodiment, the shell comprises a material selected fromwater soluble or water swellable thermoplastic film formers, watersoluble or water swellable thickeners, crystallizable andnon-crystallizable carbohydrates.

In another embodiment, the core annular portion has the shape of atorus.

In yet another embodiment, the dosage form of this invention comprises:(a) at least one active ingredient; (b) a core having an outer surfaceand a cavity which extends at least partially through the core such thatthe core outer surface has at least a first opening therein; (c) a firstcoating which resides on at least a portion of the core outer surface,wherein the first shell portion comprises a different material from thefirst coating; and (d) a first shell portion which is adjacent to thefirst opening and covers at least the first opening.

In another embodiment, the cavity extends entirely through the core suchthat the core has first and second openings therein, the first shellportion is adjacent to and covers at least the first opening, and thedosage form additionally comprises a second shell portion which isadjacent to and covers at least the second opening, wherein the firstand second shell portions each comprise a material different from thefirst coating.

In another embodiment, the core has the shape of a torus.

In another embodiment, the first shell portion comprises at least onewater soluble material.

In another embodiment, the second shell portion comprises at least onewater soluble material.

In another embodiment, the first and second shell portions each compriseat least one water soluble material.

In another embodiment, the first shell portion or the core or acombination thereof comprises at least one active ingredient.

In another embodiment, the first shell portion, second shell portion orthe core or a combination thereof comprises at least one activeingredient.

In another embodiment, the first shell portion resides upon at least aportion of the first coating.

In another embodiment, the shell resides upon the entire outer surfaceof the first coating.

In another embodiment, at least a portion of the active ingredient isreleased in a sustained manner.

In another embodiment, the dosage form releases at least a portion ofthe active ingredient at a substantially constant rate.

In another embodiment, the release of at least one active ingredientfrom the center portion of the core meets USP specifications forimmediate release tablets containing the particular active ingredientemployed.

In another embodiment, the center portion of the core provides a timedelay to the release of active ingredient from the annular portion ofthe core.

In another embodiment, the core functions as an eroding matrix.

In another embodiment, the core functions as a diffusional matrix.

In another embodiment, the core comprises a release-modifying excipientselected from the group consisting of swellable erodible hydrophillicmaterials, insoluble edible materials, pH-dependent polymers, andmixtures thereof.

In another embodiment, the first coating comprises at least about 30weight percent of a thermal reversible carrier, based on the weight ofthe first coating.

In another embodiment, the first coating comprises at lease about 10weight percent of a film former selected from the group consisting offilm-forming water soluble polymers, film-forming proteins, film-formingwater insoluble polymers, and film-forming pH-dependent polymers.

In another embodiment, the film-former for making the core or shell orportion thereof by molding may be selected from cellulose acetate,ammonio methacrylate copolymer type B, shellac,hydroxypropylmethylcellulose, and polyethylene oxide, and combinationsthereof.

In another embodiment, the shell or shell portion comprisesthermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides,and combinations thereof.

In another embodiment, the shell portion is breached or dissolved within30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at37° C. with stirring by a USP type 2 (Paddle method) at 50 or 100 rpm.

In another embodiment, the release of at least one active ingredientfollows a double pulse profile.

In another embodiment, the release of at least one active ingredientfollows a delayed then sustained release profile.

In another embodiment, release of a first portion of active ingredientfrom the dosage form meets USP specifications for immediate releasetablets containing the particular active ingredient employed, andrelease of a second portion of active ingredient from the dosage formfollows a sustained, prolonged, extended, or retarded release profile.

In another embodiment, the immediately released first portion of activeingredient is contained in the shell, and the sustained release secondportion of active ingredient is contained in the core.

In another embodiment, the release of one or more active ingredientsfollows a zero-order, first-order, or square root of time profile.

In another embodiment, the shell is substantially free of pores in thediameter range of 0.5 to 5.0 microns.

In yet another embodiment, this invention provides a method of applyinga partial coating to a core in a dosage form by thermal cycle molding.

In yet another embodiment, this invention provides a method of applyinga partial coating to a core in a dosage form by thermal setting molding.

In yet another embodiment, the first coating comprises up to about 55weight percent of a release-modifying excipient selected fromwater-insoluble polymers and low-melting hydrophobic materials andcombinations thereof.

In yet another embodiment, the release-modifying excipeint is apolycaprolactone.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict overhead and side views of one embodiment of thedosage form of this invention.

FIGS. 2A and 2B depict overhead and side views of another embodiment ofthe dosage form of this invention.

FIGS. 3A and 3B depict overhead and side views of another embodiment ofthe dosage form of this invention.

FIGS. 4A and 4B depict overhead and side views of another embodiment ofthe dosage form of this invention.

FIGS. 5A and 5B depict overhead and side views of another embodiment ofthe dosage form of this invention.

FIG. 6 depicts the % release of active ingredient vs. hours measured forthe dosage form of Example 1.

FIGS. 7A and 7B depict another embodiment of a dosage form according tothe invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “dosage form” applies to any solid object,semi-solid, or liquid composition designed to contain a specificpre-determined amount (i.e. dose) of a certain ingredient, for examplean active ingredient as defined below. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery, or subcutaneous implants, or other implanted drugdelivery systems; or compositions for delivering minerals, vitamins andother nutraceuticals, oral care agents, flavorants, and the like.Preferably the dosage forms of the present invention are considered tobe solid, however they may contain liquid or semi-solid components. In aparticularly preferred embodiment, the dosage form is an orallyadministered system for delivering a pharmaceutical active ingredient tothe gastro-intestinal tract of a human.

The dosage forms of the present invention contain one or more activeingredients which are released therefrom upon contact of the dosage formwith a liquid medium, for example a dissolution medium. Examples ofsuitable dissolution media for the dosage form of the invention includegastrointestinal fluids for embodiments in which the dosage form isorally ingested, mucosal fluids for embodiments in which the dosage formis for buccal delivery, intracellular fluids for embodiments in whichthe dosage form is an implant, moisture in the soil for embodiments inwhich the dosage form delivers a fertilizer or plant nutrient, andsynthetic dissolution media, e.g. water or aqueous buffer solutions, fortesting the performance of the dosage form in vitro.

“Water soluble,” as used herein in connection with non-polymericmaterials, shall mean from sparingly soluble to very soluble, i.e., notmore than 100 parts water required to dissolve 1 part of thenon-polymeric, water soluble solute. See Remington, The Science andPractice of Pharmacy, pp 208-209 (2000). “Water soluble,” as used hereinin connection with polymeric materials, shall mean that the polymerswells in water and can be dispersed at the molecular level to form ahomogeneous dispersion or colloidal “solution.”

The dosage forms of the invention exhibit modified release of one ormore active ingredients contained therein. One or more activeingredients may be found in any portion of the dosage form, for exampleone or more active ingredients may be found within the core, the centerportion, the shell portion, or coated or uncoated particles distributedtherethrough. As used herein, the term “modified release” shall apply todosage forms, matrices, particles, coatings, portions thereof, orcompositions that alter the release of an active ingredient in anymanner. Types of modified release include controlled, prolonged,sustained, extended, delayed, pulsatile, repeat action, and the like.Suitable mechanisms for achieving these types of modified releaseinclude diffusion, erosion, surface area control via geometry and/orimpermeable barriers, or other mechanisms known in the art. Moreover,the modified release properties of the dosage form may be achievedthrough design of the core or a portion thereof, or the first coating,or the shell portion, or a combination of two or more of these parts ofthe dosage form.

In certain particularly preferred embodiments of this invention, thedosage form releases one or more active ingredients contained therein ina controlled manner, e.g. in a sustained, extended, prolonged, orretarded manner, more preferably at a substantially constant rate uponcontacting of the dosage form with a liquid medium. In such embodiments,the core or center portion or shell or a portion thereof may function asa diffusional matrix or an eroding matrix.

The dosage form of the invention comprises a first coating which residesupon a first surface portion of the core. In certain embodiments, thefirst coating may function as a barrier to prevent release therethroughof an active ingredient contained in the underlying core portion. Insuch embodiments, active ingredient is typically released from a portionof the core which is not covered by the barrier coating portion. Suchembodiments advantageously allow for control of the surface area forrelease of the active ingredient. In certain particular embodiments, forexample, the surface area for release of active ingredient can bemaintained substantially constant over time In certain other particularembodiments, for example, the surface area for release of activeingredient can increase over time during the dissolution period of thedosage form. The surface area for release of active ingredient may becontrolled by a combination of the size of the uncoated area on the coresurface, and the overall shape of the core. In certain such embodiments,the barrier coating preferably comprises a water insoluble material suchas for example a water insoluble polymer. Since surface area is onefactor in the dissolution equation, controlling surface area for drugrelease advantageously enables a further degree of control over therelease rate of the drug from the dosage form. In a particularlypreferred embodiment, the release of at least one active ingredientfollows substantially zero-order kinetics.

The dosage form also comprises a shell or shell portion that resides on(i.e., directly contacts) or covers (i.e., shields or screens but doesnot necessarily directly contact) at least a portion of the exteriorsurface of the core where no first coating is present. The shell mayreside on or cover the entire portion of the core free of first coating.Alternately the shell may reside on only a portion of the uncoated coresurface. Additionally, the shell may cover all, none, or a portion ofthe first coating as well. In a particularly preferred embodiment theshell resides upon only the portion of the core free of first coating,and does not contact the first coating. In another embodiment, the shellcovers the entire portion of the core free of first coating, andconnects with the first coating at an interface, but does notsubstantially cover the first coating. In yet another embodiment, theshell covers both the entire portion of the core free of first coatingand the entire first coating. The shell comprises a material that isdifferent from the first coating.

In certain embodiments in which the shell comprises the overall outersurface of the dosage form, the shell is preferably of a smooth overallshape, e.g. a spheroid, ellypsoid, or other easily swallowable shapesuch as those having rounded edges. Accordingly, the dosage form resistsdamage during transport and handling and is easy to swallow, despite theshape of the core inside.

A first embodiment of this invention is depicted in FIGS. 1A and 1B.FIG. 1A depicts an overhead view and FIG. 1B depicts a side view of adosage form 2 which comprises a core 4 having a first surface portion 6and second surface portions 8. A first coating 10 resides upon the firstsurface portion 6 of core 4. However, the second surface portion 8 ofcore 4 is substantially free of first coating 10. A shell 12 residesupon the second surface portion 8 of core 4.

Optionally, core 4 of the dosage form depicted in FIGS. 1A and 1B maycontain a cavity as shown in FIGS. 2A and 2B, which respectively depictoverhead and side views of a dosage form 202 which comprises a core 204having a first surface portion 206, a cavity 205 and a second surfaceportion 208. A first coating 210 resides upon the first surface portion206 of core 204. The second surface portion 208 of core 204 is definedat least in part by cavity 205 and the second surface portion 208 issubstantially free of first coating 210. A shell 212 resides upon thesecond surface portion 208 of core 204.

Another embodiment of this invention is depicted in FIGS. 3A and 3B,which depict a further variation of the dosage form of FIGS. 1A and 1B.FIGS. 3A and 3B depict overhead and side views of a dosage form 302which comprises a core 304 having a first surface portion 306, anaperture 305 which extends completely through core 304 and a secondsurface portion 308. The second surface portion 308 of core 304 isdefined by aperture 305. A first coating 310 resides upon the firstsurface portion 306 of core 304. Again, the second surface portion 308is substantially free of first coating 310. A shell 312 resides upon thesecond surface portion 308 of core 304.

Another embodiment of this invention is depicted in FIGS. 4A and 4B,which depict overhead and side views of dosage form 402, which comprisesa core 404 made up of a center portion 405 surrounded by an annularportion 409. The center portion 405 has a surface 407, while the annularportion 409 has an exterior surface 411 and an interior surface 413. Theannular portion interior surface 413 is in contact with a portion of thecenter portion surface 407. The annular portion exterior surface 410 iscovered by a first coating 410. A shell, divided into first and secondshell portions 415 reside upon a portion of the center portion surface407

Another embodiment of this invention is depicted in FIGS. 5A and 5B,which depict overhead and side views of dosage form 502 which comprisesa core 504 having an outer surface 506 and an inner surface 508 that isdefined by an aperture 505 extending completely through the core 504. Afirst coating 510 resides upon the outer surface 506 of core 504. Theinner surface 508 is substantially free of first coating 510. A firstshell portion 513 covers one end of the aperture 505, and a second shellportion 515 covers the opposite end of the aperture 505. Accordingly, avoid is created inside the dosage form.

FIG. 7A depicts another embodiment of the invention. In this embodiment,the dosage form 702 comprises a core 704 having the shape of a torus.This shape has been found to be especially conducive to controlledrelease of an active ingredient. The core 704 has an outer surface 706and an inner surface 708 that is defined by an aperture 705. A firstcoating 710 resides on the outer surface 706 of the core 704, as shownin FIG. 7B. The inner surface 708 is substantially free of first coating710. A shell 715 encloses the entire core 704 and first coating 710. Theshell 715 has a generally elliptical shape.

Suitable active ingredients for use in this invention include forexample pharmaceuticals, minerals, vitamins and other nutraceuticals,oral care agents, flavorants and mixtures thereof. Suitablepharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, contraceptives, diuretics, expectorants,gastrointestinal agents, migraine preparations, motion sicknessproducts, mucolytics, muscle relaxants, osteoporosis preparations,polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tractagents and mixtures thereof.

Suitable oral care agents include breath fresheners, tooth whiteners,antimicrobial agents, tooth mineralizers, tooth decay inhibitors,topical anesthetics, mucoprotectants, and the like.

Suitable flavorants include menthol, peppermint, mint flavors, fruitflavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueurflavors and combinations and the like.

Examples of suitable gastrointestinal agents include antacids such ascalcium carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminumsodium carbonate; stimulant laxatives, such as bisacodyl, cascarasagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleicacid, and dehydrocholic acid, and mixtures thereof; H2 receptorantagonists, such as famotadine, ranitidine, cimetadine, nizatidine;proton pump inhibitors such as omeprazole or lansoprazole;gastrointestinal cytoprotectives, such as sucraflate and misoprostol;gastrointestinal prokinetics, such as prucalopride, antibiotics for H.pylori, such as clarithromycin, amoxicillin, tetracycline, andmetronidazole; antidiarrheals, such as diphenoxylate and loperamide;glycopyrrolate; antiemetics, such as ondansetron, analgesics, such asmesalamine.

In one embodiment of the invention, the active agent may be selectedfrom bisacodyl, famotadine, ranitidine, cimetidine, prucalopride,diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

In another embodiment, the active agent is selected from analgesics,anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including propionic acid derivatives,e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acidderivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and thelike; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid,flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam,sudoxicam, isoxicam, meloxicam, and the like. In a particularlypreferred embodiment, the active agent is selected from propionic acidderivative NSAIDs, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts,derivatives, and combinations thereof. In a particular embodiment of theinvention, the active agent may be selected from acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

In another embodiment of the invention, the active agent may be selectedfrom pseudoephedrine, phenylpropanolamine, chlorpheniramine,dextromethorphan, diphenhydramine, astemizole, terfenadine,fexofenadine, loratadine, desloratidine, doxilamine, norastemizole,cetirizine, mixtures thereof and pharmaceutically acceptable salts,esters, isomers, and mixtures thereof.

Examples of suitable polydimethylsiloxanes, which include, but are notlimited to dimethicone and simethicone, are those disclosed in U.S. Pat.Nos. 4,906,478, 5,275,822, and 6,103,260. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

The active ingredient or ingredients are present in the dosage form in atherapeutically effective amount, which is an amount that produces thedesired therapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular active ingredient being administered, the bioavailabilitycharacteristics of the active ingredient, the dose regime, the age andweight of the patient, and other factors must be considered, as known inthe art. Preferably, the dosage form comprises at least about 85 weightpercent of the active ingredient. In one preferred embodiment, the corecomprises at least about 85 weight percent of the active ingredient.

The active ingredient or ingredients may be present in the dosage formin any form. For example, the active ingredient may be dispersed at themolecular level, e.g. melted or dissolved, within the dosage form, ormay be in the form of particles, which in turn may be coated oruncoated. If the active ingredient is in form of particles, theparticles (whether coated or uncoated) typically have an averageparticle size of about 1-2000 microns. In one preferred embodiment, suchparticles are crystals having an average particle size of about 1-300microns. In another preferred embodiment, the particles are granules orpellets having an average particle size of about 50-2000 microns,preferably about 50-1000 microns, most preferably about 100-800 microns.

In embodiments where an active ingredient is contained within the core,at least a portion of the active ingredient may be optionally coatedwith a release-modifying coating, as known in the art. Thisadvantageously provides an additional tool for modifying the releaseprofile of the dosage form. In particular embodiments of this inventionin which coated particles are employed, the particles may be asdescribed herein, and the particles may be coated using conventionalcoating technology which is well known to those skilled in the artincluding microencapsulation techniques such as coacervation,spray-drying, and fluidized bed coating including tangential spray rotorcoating and bottom spray wurster coating. Examples of suitable particlecoating methods and materials can be found in U.S. Pat. Nos. 5,286,497;4,863,742; 4,173,626; 4,980,170; 4,984,240; 5,912,013; 6,270,805; and6,322,819.

In embodiments in which it is desired for the active ingredient to beabsorbed into the systemic circulation of an animal, the activeingredient or ingredients are preferably capable of dissolution uponcontact with a fluid such as water, gastric fluid, intestinal fluid orthe like. In one embodiment, the dissolution characteristics of at leastone active ingredient meets USP specifications for immediate releasetablets containing the active ingredient. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the ibuprofen contained in the dosage form is released therefromwithin 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856(1999). In embodiments in which at least one active ingredient isreleased immediately, the immediately released active ingredient ispreferably contained in the shell or on the surface of the shell, e.g.in a further coating surrounding at least a portion of the shell. Inanother embodiment, the dissolution characteristics of one or moreactive ingredients are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like. In a preferred embodiment inwhich one or more active ingredients are released in a modified manner,the modified release active or actives are preferably contained in thecore.

The core of the present invention may be prepared by any suitablemethod, including for example compression and molding, and depending onthe method by which it is made, typically comprises, in addition to theactive ingredient, a variety of excipients (inactive ingredients whichmay be useful for conferring desired physical properties to the dosageform).

In a preferred embodiment, the core is prepared by the compressionmethods and apparatus described in copending U.S. patent applicationSer. No. 09/966,509, pages 16-27, the disclosure of which isincorporated herein by reference. Specifically, the core is made using arotary compression module comprising a fill zone, insertion zone,compression zone, ejection zone, and purge zone in a single apparatushaving a double row die construction as shown in FIG. 6 of U.S. patentapplication Ser. No. 09/966,509. The dies of the compression module arepreferably filled using the assistance of a vacuum, with filters locatedin or near each die. The purge zone of the compression module includesan optional powder recovery system to recover excess powder from thefilters and return excess powder to the dies.

In embodiments in which the core, or a portion thereof, is made bycompression, suitable excipients include fillers, binders,disintegrants, lubricants, glidants, and the like, as known in the art.In embodiments in which the core is made by compression, the core mayfurther comprise a release-modifying compressible excipient.

Suitable fillers for use in making the core, or a portion thereof, bycompression include water-soluble compressible carbohydrates such assugars, which include dextrose, sucrose, maltose, and lactose,sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol,starch hydrolysates, which include dextrins, and maltodextrins, and thelike, water insoluble plastically deforming materials such asmicrocrystalline cellulose or other cellulosic derivatives,water-insoluble brittle fracture materials such as dicalcium phosphate,tricalcium phosphate and the like and mixtures thereof.

Suitable binders for making the core, or a portion thereof, bycompression include dry binders such as polyvinyl pyrrolidone,hydroxypropylmethylcellulose, and the like; wet binders such aswater-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose,starches, and the like; and derivatives and mixtures thereof.

Suitable disintegrants for making the core, or a portion thereof, bycompression, include sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and the like.

Suitable lubricants for making the core, or a portion thereof, bycompression include long chain fatty acids and their salts, such asmagnesium stearate and stearic acid, talc, glycerides and waxes.

Suitable glidants for making the core, or a portion thereof, bycompression, include colloidal silicon dioxide, and the like.

Suitable release-modifying compressible excipients for making the core,or a portion thereof, by compression include swellable erodiblehydrophillic materials, insoluble edible materials, pH-dependentpolymers, and mixtures thereof.

Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or a portion thereof,by compression include: water swellable cellulose derivatives,polyalkalene glycols, thermoplastic polyalkalene oxides, acrylicpolymers, hydrocolloids, clays, gelling starches, and swellingcross-linked polymers, and derivitives, copolymers, and combinationsthereof. Examples of suitable water swellable cellulose derivativesinclude sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molecular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

Suitable insoluble edible materials for use as release-modifyingexcipients for making the core, or a portion thereof, by compressioninclude water-insoluble polymers, and low-melting hydrophobic materials.Examples of suitable water-insoluble polymers include ethylcellulose,polyvinyl alcohols, polyvinyl acetate, polycaprolactones, celluloseacetate and its derivatives, acrylates, methacrylates, acrylic acidcopolymers; and the like and derivatives, copolymers, and combinationsthereof. Suitable low-melting hydrophobic materials include fats, fattyacid esters, phospholipids, and waxes. Examples of suitable fats includehydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil; and free fatty acids andtheir salts. Examples of suitable fatty acid esters include sucrosefatty acid esters, mono, di, and triglycerides, glyceryl behenate,glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate,glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroylmacrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples ofsuitable phospholipids include phosphotidyl choline, phosphotidylserene, phosphotidyl enositol, and phosphotidic acid. Examples ofsuitable waxes include carnauba wax, spermaceti wax, beeswax, candelillawax, shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; and the like.

Suitable pH-dependent polymers for use as release-modifying excipientsfor making the core, or a portion thereof, by compression includeenteric cellulose derivatives, for example hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate phthalate; natural resins such as shellac and zein; entericacetate derivatives such as for example polyvinylacetate phthalate,cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; andenteric acrylate derivatives such as for example polymethacrylate-basedpolymers such as poly(methacrylic acid, methyl methacrylate) 1:2, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT L; and the like, and derivatives, salts, copolymers, andcombinations thereof.

Suitable pharmaceutically acceptable adjuvants for making the core, or aportion thereof, by compression include, preservatives; high intensitysweeteners such as aspartame, acesulfame potassium, sucralose, andsaccharin; flavorants; colorants; antioxidants; surfactants; wettingagents; and the like and mixtures thereof.

The core or a portion thereof may also be formed by molding, usingeither a solvent free, or solvent based method.

In another embodiment, the core is prepared by thermal setting moldingusing the method and apparatus described in copending U.S. patentapplication Ser. No. 09/966,450, pages 57-63, the disclosure of which isincorporated herein by reference. In this embodiment, the core is formedby injecting a starting material in flowable form into a moldingchamber. The starting material preferably comprises an active ingredientand a thermal setting material at a temperature above the melting pointof the thermal setting material but below the decomposition temperatureof the active ingredient. The starting material is cooled and solidifiesin the molding chamber into a shaped form (i.e., having the shape of themold).

In another embodiment, the core is prepared by thermal cycle moldingusing the method and apparatus described in copending U.S. patentapplication Ser. No. 09/966,497, pages 27-51, the disclosure of which isincorporated herein by reference. In this embodiment, the core is formedby injecting a starting material in flowable form into a heated moldingchamber. The starting material preferably comprises an active ingredientand a thermoplastic material at a temperature above the set temperatureof the thermoplastic material but below the decomposition temperature ofthe active ingredient. The starting material is cooled and solidifies inthe molding chamber into a shaped form (i.e., having the shape of themold).

The first coating may be applied to the core by known methods, such asdipping, or spraying. In a preferred embodiment, however, the firstcoating is applied to the core by molding. The first coating may bemolded using a solvent free or solvent based method, preferably usingeither the thermal cycling molding module, or thermal setting moldingmodule, as described herein. This invention advantageously achieves acost effective process for applying a partial coating to selectedportions of a core without the need for costly and complex subsequentsteps of previously known methods, such as application of a completecoating to a core, followed by removal of a portion of the core andcoating to permit selective application of another coating to a portionof the core.

In certain embodiments of the invention, the first coating may functionas a barrier to the passage of water or active ingredient therethrough.In certain other embodiments, the first coating may function as asemi-permeable membrane, allowing water or solvent to pass into thecore, but being impermeable to dissolved active ingredient, therebypreventing the passage of active ingredient therethrough. In certainother embodiments, the first coating may function as a diffusionalmembrane, allowing the passage of active ingredient therethrough at arate controlled by the thickness, porosity and tortuosity of the firstcoating. In certain other embodiments, the first coating may function asan erosional coating to provide a time delay to the release of one ormore portions of active ingredient in the core. In certain otherembodiments, the first coating may comprise one or more activeingredients. In one embodiment in which the first coating comprisesactive ingredient, the first coating may comprise a water soluble activeingredient intended for immediate release from the dosage form, whichdissolves promptly upon contact of the dosage form with a liquid medium,thereby creating pores in the first coating for the diffusion of asecond dose of active ingredient contained in the core or a portionthereof.

The first coating preferably comprises from about 10 to about 100 weightpercent of a film former. In embodiments in which the first coatingfunctions as a barrier, the film former is preferably a water insolublematerial such as for example a water insoluble polymer. In embodimentsin which the first coating functions as a semipermeable membrane,allowing water or solvent to pass into the core, but being impermeableto dissolved active ingredient, thereby preventing the passage of activeingredient therethrough, the film former is preferably selected fromwater insoluble polymers, pH-dependent polymers, water soluble polymers,and combinations thereof. In embodiments in which the first coating mayfunction as a diffusional membrane, allowing the passage of activeingredient therethrough at a rate controlled by the thickness, porosityand tortuosity of the first coating, the film former is preferablyselected from water insoluble polymers, pH-dependent polymers, andcombinations thereof, and the first coating preferably further comprisesa pore former. In embodiments in which the first coating functions as adelayed release coating to delay release of a portion of activeingredient which is contained in the core or a portion thereof, firstcoating preferably further comprises a swellable erodible hydrophilicmaterial.

The shell or shell portion of the present invention is preferablyapplied by molding, such as thermal cycle or thermal setting molding, asdescribed herein, using either a solvent free or solvent based method.The method of the invention advantageously enables a partial shell to beapplied to or deposited upon a selected area of the core and optionallythe first coating.

The shell comprises a material that is compositionally different fromthe first coating. As used herein, the term “compositionally different”means having features that are readily distinguishable by qualitative orquantitative chemical analysis, physical testing, or visual observation.For example, the first coating and shell materials may contain differentingredients, or different levels of the same ingredients, or the firstand second materials may have different physical or chemical properties,different functional properties, or be visually distinct. Examples ofphysical or chemical properties that may be different includehydrophylicity, hydrophobicity, hygroscopicity, elasticity, plasticity,tensile strength, crystallinity, and density. Examples of functionalproperties which may be different include rate and/or extent ofdissolution of the material itself or of an active ingredient therefrom,rate of disintegration of the material, permeability to activeingredients, permeability to water or aqueous media, and the like.Examples of visual distinctions include size, shape, topography, orother geometric features, color, hue, opacity, and gloss.

For example the first coating and shell may comprise different types orlevels of colorants, opacifiers, film-formers, etc. Alternatively, thefirst coating and shell may have different thickness. The first coatingand shell may have different functionalities. For example, the firstcoating and shell may confer different release properties to an activeingredient contained in either the subject coating or shell, or in acorresponding underlying core portion. In one particular embodiment, thefirst coating may function as a barrier to the passage therethrough ofone or more active ingredients contained in the underlying core portion;and the shell may function as an eroding matrix from which activeingredient dispersed in the shell or shell portion is liberated by thedissolution of successive layers of the shell portion surface.

In certain preferred embodiments of the invention, the core, or thefirst coating, or the shell, or a portion thereof, is prepared bymolding. In such embodiments, the core, or the shell, or a portionthereof, comprises a flowable material. The flowable material may be anyedible material that is flowable at a temperature between about 37° C.and 250° C., and that is solid, semi-solid, or can form a gel at atemperature between about −10° C. and about 35° C. When it is in thefluid or flowable state, the flowable material may comprise a dissolvedor molten component, and optionally a solvent such as for example wateror organic solvents, or combinations thereof. The solvent may bepartially or substantially removed by drying.

Suitable flowable materials for making the core, or the first coating orthe shell, or a portion thereof by molding include those comprisingthermoplastic materials; film formers; thickeners such as gellingpolymers or hydrocolloids; low melting hydrophobic materials such asfats and waxes; non-crystallizable carbohydrates; and the like. Suitablemolten components of the flowable material include thermoplasticmaterials, low melting hydrophobic materials, and the like. Suitabledissolved components for the flowable material include film formers,thickeners such as gelling polymers or hydrocolloids, non-crystallizablecarbohydrates, and the like.

Suitable thermoplastic materials can be molded and shaped when heated,and include both water soluble and water insoluble polymers that aregenerally linear, not crosslinked, nor strongly hydrogen bonded toadjacent polymer chains. Examples of suitable thermoplastic materialsinclude: thermoplastic water swellable cellulose derivatives,thermoplastic water insoluble cellulose derivatives, thermoplastic vinylpolymers, thermoplastic starches, thermoplastic polyalkalene glycols,thermoplastic polyalkalene oxides, and amorphous sugar-glass, and thelike, and derivatives, copolymers, and combinations thereof. Examples ofsuitable thermoplastic water swellable cellulose derivatives includehydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC),methyl cellulose (MC). Examples of suitable thermoplastic waterinsoluble cellulose derivatives include cellulose acetate (CA), ethylcellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate.Examples of suitable thermoplastic vinyl polymers include polyvinylalcohol (PVA) and polyvinyl pyrrolidone (PVP). Examples of suitablethermoplastic starches include those disclosed in U.S. Pat. No.5,427,614, which is incorporated herein by reference. Examples ofsuitable thermoplastic polyalkalene glycols include polyethylene glycol;Examples of suitable thermoplastic polyalkalene oxides includepolyethylene oxide having a molecular weight from about 100,000 to about900,000 Daltons. Other suitable thermoplastic materials include sugar inthe form on an amorphous glass such as that used to make hard candyforms.

Any film former known in the art is suitable for use in the flowablematerial of the present invention. Examples of suitable film formersinclude, but are not limited to, film-forming water soluble polymers,film-forming proteins, film-forming water insoluble polymers, andfilm-forming pH-dependent polymers. In one embodiment, the film-formerfor making the core or shell or portion thereof by molding may beselected from cellulose acetate, ammonio methacrylate copolymer type B,shellac, hydroxypropylmethylcellulose, and polyethylene oxide, andcombinations thereof.

Suitable film-forming water soluble polymers include water soluble vinylpolymers such as polyvinylalcohol (PVA); water soluble polycarbohydratessuch as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethylstarch, carboxymethyl starch, pre-gelatinized starches, and film-formingmodified starches; water swellable cellulose derivatives such ashydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC),methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC),hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC),and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water solublecopolymers such as methacrylic acid and methacrylate ester copolymers,polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxideand polyvinylpyrrolidone copolymers; and derivatives and combinationsthereof.

Suitable film-forming proteins may be natural or chemically modified,and include gelatin, whey protein, myofibrillar proteins, coaggulatableproteins such as albumin, casein, caseinates and casein isolates, soyprotein and soy protein isolates, zein; and polymers, derivatives andmixtures thereof.

Suitable film-forming water insoluble polymers, include for exampleethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers; and the like and derivatives,copolymers, and combinations thereof.

Suitable film-forming pH-dependent polymers include enteric cellulosederivatives, such as for example hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate phthalate; natural resins, such as shellac and zein; entericacetate derivatives such as for example polyvinylacetate phthalate,cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; andenteric acrylate derivatives such as for example polymethacrylate-basedpolymers such as poly(methacrylic acid, methyl methacrylate) 1:2, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT L; and the like, and derivatives, salts, copolymers, andcombinations thereof.

One suitable hydroxypropylmethylcellulose compound for use as athermoplastic film-forming water soluble polymer is HPMC 2910, which isa cellulose ether having a degree of substitution of about 1.9 and ahydroxypropyl molar substitution of 0.23, and containing, based upon thetotal weight of the compound, from about 29% to about 30% methoxylgroups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910is commercially available from the Dow Chemical Company under thetradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910suitable for use in the present invention, has a viscosity of about 4 to6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution asdetermined by a Ubbelohde viscometer. Similarly, METHOCEL E6; which isanother grade of HPMC-2910 suitable for use in the present invention,has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20°C. in a 2% aqueous solution as determined by a Ubbelohde viscometer.METHOCEL E15, which is another grade of HPMC-2910 suitable for use inthe present invention, has a viscosity of about 15000 cps (15millipascal-seconds) at 20° C. in a 2% aqueous solution as determined bya ubbelohde viscometer. As used herein, “degree of substitution” shallmean the average number of substituent groups attached to aanhydroglucose ring, and “hydroxypropyl molar substitution” shall meanthe number of moles of hydroxypropyl per mole anhydroglucose.

One suitable polyvinyl alcohol and polyethylene glycol copolymer iscommercially available from BASF Corporation under the tradenameKOLLICOAT IR.

As used herein, “modified starches” include starches that have beenmodified by crosslinking, chemically modified for improved stability oroptimized performance, or physically modified for improved solubilityproperties or optimized performance. Examples of chemically-modifiedstarches are well known in the art and typically include those starchesthat have been chemically treated to cause replacement of some of itshydroxyl groups with either ester or ether groups. Crosslinking, as usedherein, may occur in modified starches when two hydroxyl groups onneighboring starch molecules are chemically linked. As used herein,“pre-gelatinized starches” or “instantized starches” refers to modifiedstarches that have been pre-wetted, then dried to enhance theircold-water solubility. Suitable modified starches are commerciallyavailable from several suppliers such as, for example, A.E. StaleyManufacturing Company, and National Starch & Chemical Company. Onesuitable film forming modified starch includes the pre-gelatinized waxymaize derivative starches that are commercially available from NationalStarch & Chemical Company under the tradenames PURITY GUM and FILMSET,and derivatives, copolymers, and mixtures thereof. Such waxy maizestarches typically contain, based upon the total weight of the starch,from about 0 percent to about 18 percent of amylose and from about 100%to about 88% of amylopectin.

Another suitable film forming modified starch includes thehydroxypropylated starches, in which some of the hydroxyl groups of thestarch have been etherified with hydroxypropyl groups, usually viatreatment with propylene oxide. One example of a suitable hydroxypropylstarch that possesses film-forming properties is available from GrainProcessing Company under the tradename, PURE-COTE B790.

Suitable tapioca dextrins for use as film formers include thoseavailable from National Starch & Chemical Company under the tradenamesCRYSTAL GUM or K-4484, and derivatives thereof such as modified foodstarch derived from tapioca, which is available from National Starch andChemical under the tradename PURITY GUM 40, and copolymers and mixturesthereof.

Any thickener known in the art is suitable for use in the flowablematerial of the present invention. Examples of such thickeners includebut are not limited to hydrocolloids (also referred to herein as gellingpolymers), clays, gelling starches, and crystallizable carbohydrates,and derivatives, copolymers and mixtures thereof.

Examples of suitable hydrocolloids (also referred to herein as gellingpolymers) such as alginates, agar, guar gum, locust bean, carrageenan,tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin,chitosan. Examples of suitable clays include smectites such asbentonite, kaolin, and laponite; magnesium trisilicate, magnesiumaluminum silicate, and the like, and derivatives and mixtures thereof.Examples of suitable gelling starches include acid hydrolyzed starches,and derivatives and mixtures thereof. Additional suitable thickeninghydrocolloids include low-moisture polymer solutions such as mixtures ofgelatin and other hydrocolloids at water contents up to about 30%, suchas for example those used to make “gummi” confection forms.

Additional suitable thickeners include crystallizable carbohydrates, andthe like, and derivatives and combinations thereof. Suitablecrystallizable carbohydrates include the monosaccharides and theoligosaccharides. Of the monosaccharides, the aldohexoses e.g., the Dand L isomers of allose, altrose, glucose, mannose, gulose, idose,galactose, talose, and the ketohexoses e.g., the D and L isomers offructose and sorbose along with their hydrogenated analogs: e.g.,glucitol (sorbitol), and mannitol are preferred. Of theoligosaccharides, the 1,2-disaccharides sucrose and trehalose, the1,4-disaccharides maltose, lactose, and cellobiose, and the1,6-disaccharides gentiobiose and melibiose, as well as thetrisaccharide raffinose are preferred along with the isomerized form ofsucrose known as isomaltulose and its hydrogenated analog isomalt. Otherhydrogenated forms of reducing disaccharides (such as maltose andlactose), for example, maltitol and lactitol are also preferred.Additionally, the hydrogenated forms of the aldopentoses: e.g., D and Lribose, arabinose, xylose, and lyxose and the hydrogenated forms of thealdotetroses: e.g., D and L erythrose and threose are preferred and areexemplified by xylitol and erythritol, respectively.

In one embodiment of the invention, the flowable material comprisesgelatin as a gelling polymer. Gelatin is a natural, thermogellingpolymer. It is a tasteless and colorless mixture of derived proteins ofthe albuminous class which is ordinarily soluble in warm water. Twotypes of gelatin—Type A and Type B—are commonly used. Type A gelatin isa derivative of acid-treated raw materials. Type B gelatin is aderivative of alkali-treated raw materials. The moisture content ofgelatin, as well as its Bloom strength, composition and original gelatinprocessing conditions, determine its transition temperature betweenliquid and solid. Bloom is a standard measure of the strength of agelatin gel, and is roughly correlated with molecular weight. Bloom isdefined as the weight in grams required to move a half-inch diameterplastic plunger 4 mm into a 6.67% gelatin gel that has been held at 10°C. for 17 hours. In a preferred embodiment, the flowable material is anaqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250Bloom Bone Gelatin, and approximately 60% water.

Suitable xanthan gums include those available from C.P. Kelco Companyunder the tradenames KELTROL 1000, XANTROL 180, or K9B310.

Suitable clays include smectites such as bentonite, kaolin, andlaponite; magnesium trisilicate, magnesium aluminum silicate, and thelike, and derivatives and mixtures thereof.

“Acid-hydrolyzed starch,” as used herein, is one type of modified starchthat results from treating a starch suspension with dilute acid at atemperature below the gelatinization point of the starch. During theacid hydrolysis, the granular form of the starch is maintained in thestarch suspension, and the hydrolysis reaction is ended byneutralization, filtration and drying once the desired degree ofhydrolysis is reached. As a result, the average molecular size of thestarch polymers is reduced. Acid-hydrolyzed starches (also known as“thin boiling starches”) tend to have a much lower hot viscosity thanthe same native starch as well as a strong tendency to gel when cooled.

“Gelling starches,” as used herein, include those starches that, whencombined with water and heated to a temperature sufficient to form asolution, thereafter form a gel upon cooling to a temperature below thegelation point of the starch. Examples of gelling starches include, butare not limited to, acid hydrolyzed starches such as that available fromGrain Processing Corporation under the tradename PURE-SET B950;hydroxypropyl distarch phosphate such as that available from GrainProcessing Corporation under the tradename, PURE-GEL B990, and mixturesthereof.

Suitable low-melting hydrophobic materials include fats, fatty acidesters, phospholipids, and waxes. Examples of suitable fats includehydrogenated vegetable oils such as for example cocoa butter,hydrogenated palrn kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil; and free fatty acids andtheir salts. Examples of suitable fatty acid esters include sucrosefatty acid esters, mono, di, and triglycerides, glyceryl behenate,glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate,glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroylmacrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples ofsuitable phospholipids include phosphotidyl choline, phosphotidylserene, phosphotidyl enositol, and phosphotidic acid. Examples ofsuitable waxes include carnauba wax, spermaceti wax, beeswax, candelillawax, shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; and the like.

Suitable non-crystallizable carbohydrates include non-crystallizablesugars such as polydextrose, and starch hydrolysates, e.g. glucosesyrup, corn syrup, and high fructose corn syrup; and non-crystallizablesugar-alcohols such as maltitol syrup.

Suitable solvents for optional use as components of the flowablematerial include water; polar organic solvents such as methanol,ethanol, isopropanol, acetone, and the like; and non-polar organicsolvents such as methylene chloride, cyclohexane, and the like; andmixtures thereof.

The flowable material may optionally comprise adjuvants or excipients,which may comprise up to about 30% by weight of the flowable material.Examples of suitable adjuvants or excipients include plasticizers,detackifiers, humectants, surfactants, anti-foaming agents, colorants,flavorants, sweeteners, opacifiers, and the like. Suitable plasticizersfor making the core, the shell, or a portion thereof, by moldinginclude, but not be limited to polyethylene glycol; propylene glycol;glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate;vegetable oils such as castor oil, rape oil, olive oil, and sesame oil;surfactants such as polysorbates, sodium lauryl sulfates, anddioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate ofglycerol; triacetate of glycerol; natural gums; triacetin;acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate;diethylmalonate; dioctylphthalate; dibutylsuccinate;glyceroltributyrate; hydrogenated castor oil; fatty acids; substitutedtriglycerides and glycerides; and the like and/or mixtures thereof. Inone embodiment, the plasticizer is triethyl citrate. In certainembodiments, the shell is substantially free of plasticizers, i.e.contains less than about 1%, say less than about 0.01% of plasticizers.

In one preferred embodiment, the flowable material comprises less than5% humectants, or alternately is substantially free of humectants, suchas glycerin, sorbitol, maltitol, xylitol, or propylene glycol.Humectants have traditionally been included in pre-formed films employedin enrobing processes, such as that disclosed in U.S. Pat. Nos.5,146,730 and 5,459,983, to ensure adequate flexibility or plasticityand bondability of the film during processing. Humectants function bybinding water and retaining it in the film. Pre-formed films used inenrobing processes can typically comprise up to 45% water.Disadvantageously, the presence of humectant prolongs the dryingprocess, and can adversely affect the stability of the finished dosageform.

In certain particularly preferred embodiments of the invention, thecore, or the first coating, or the shell, or portions thereof may bemolded using a solvent-free process. In certain such embodiments, thecore, or the first coating, or the shell, or portions thereof maycomprise active ingredient contained within a molded excipient matrix.In other such embodiments, the core, or the first coating, or the shell,or portions thereof may comprise a molded excipient matrix substantiallyfree of active ingredient. The molded matrix typically comprises atleast about 30 weight percent of a thermal-reversible carrier. Themolded matrix may optionally further comprise up to about 55 weightpercent of one or more release-modifying moldable excipients asdescribed below, and optionally up to about 30 weight percent of variousadjuvants such as for example plasticizers, gelling agents, colorants,stabilizers, preservatives, and the like as known in the art.

In certain other particularly preferred embodiments of the invention,the core or the first coating or the shell or a portion or portionsthereof are prepared using a solvent-based molding process, the moldedcore or coating or shell or portion will typically comprise at leastabout 10 weight percent, e.g. at least about 12 weight percent or atleast about 15 weight percent or at least about 20 weight percent or atleast about 25 weight percent of a film-former. Here, the solvent-moldedshell portion or portions may optionally further comprise up to about 55weight percent of a release-modifying excipient. The solvent-moldedshell portion or portions may again also optionally further comprise upto about 30 weight percent total of various plasticizers, adjuvants, andexcipients.

In certain embodiments in which one or more active ingredients containedin the core are released from the dosage form in a controlled marner,the core, or a portion thereof may function as a diffusional matrix. Inthese embodiments, the core or core portion preferably comprises activeingredient, distributed throughout an insoluble porous matrix, whichcontains pores or channels through which fluids can enter the core orcore portion, and the active ingredient must diffuse in order to bereleased from the dosage form. In these embodiments, the rate of activeingredient release from the core portion will depend upon the area (A)of the matrix, the diffusion coefficient (D), the porosity (E) andtortuosity (T) of the matrix, the drug solubility (Cs) in thedissolution medium, and the drug concentration (Cp) in the dosage form.In preferred embodiments in which a core portion functions as adiffusional matrix, the release of the active ingredient from the coreor core portion may be described as controlled, prolonged, sustained, orextended. In these embodiments, the contribution to active ingredientdissolution from the subject core portion may follow zero-order,first-order, or preferably square-root of time kinetics. In theseembodiments, the core may be made by compression or molding. Inembodiments in which the core or portion thereof functions as adiffusional matrix through which active ingredient contained therein isliberated in a sustained, extended, prolonged, or retarded manner, thecore or core portion preferably comprises a release-modifying excipientselected from combinations of insoluble edible materials and poreformers. Alternately, in such embodiments in which the core or coreportion is prepared by solvent-free molding, the thermal-reversiblecarrier may function by dissolving and forming pores or channels throughwhich the active ingredient may be liberated.

In certain other embodiments in which one or more active ingredientscontained in the core are released from the dosage form in a controlledmanner, the core or portion thereof may function as an eroding matrixfrom which active ingredient dispersed in the core or core portion isliberated by the dissolution of successive layers of the core or coreportion surface. In these embodiments, the rate of active ingredientrelease will depend on the dissolution rate of the matrix material inthe core or core portion. Particularly useful matrix materials forproviding surface erosion include those that first absorb liquid, thenswell and/or gel prior to dissolving. In embodiments in which the coreor portion thereof functions as an eroding matrix from which dispersedactive ingredient is liberated in a sustained, extended, prolonged, orretarded manner, the core or core portion may be made by compression orby molding, and the core or core portion preferably comprises arelease-modifying excipient selected from swellable erodible hydrophilicmaterials, pH-dependent polymers, insoluble edible materials, andcombinations thereof. In certain particular such embodiments, theeroding matrix core or core portion preferably comprises a swellableerodible hydrophilic material.

In certain preferred embodiments of the invention, one or more shellportions contain active ingredient which is released essentiallyimmediately upon ingestion of the dosage form. In these embodiments, theshell portion preferably comprises materials which exhibit rapiddissolution in gastro-intestinal fluids.

In certain other embodiments, one or more shell portions function as adiffusional membrane which contains pores through which fluids can enterthe dosage form, and dissolved active ingredient can be released. Inthese embodiments, the rate of release of active ingredient from anunderlying core portion will depend upon the total pore area in theshell portion, the pathlength of the pores, and the solubility anddiffusivity of the active ingredient (in addition to its rate of releasefrom the core portion itself). In preferred embodiments in which a shellportion functions as a diffusional membrane, the release of the activeingredient from the dosage form may be described as controlled,prolonged, sustained or extended. In these embodiments, the contributionto active ingredient dissolution from the subject shell portion mayfollow zero-order, first-order, or square-root of time kinetics. Incertain such embodiments, the diffusional membrane shell portionpreferably comprises a pore former and an insoluble material such as forexample a film forming water insoluble polymer.

In certain other embodiments, one or more shell portions function as aneroding matrix from which active ingredient dispersed in the shellportion is liberated by the dissolution of successive layers of theshell portion surface. In these embodiments, the rate of activeingredient release will depend on the dissolution rate of the matrixmaterial in the shell portion. Particularly useful matrix materials forproviding surface erosion include those which first absorb liquid, thenswell and/or gel prior to dissolving. In certain such embodiments, theeroding matrix shell portion preferably comprises a swellable erodiblehydrophilic material.

In certain other embodiments, one or more shell portions function as abarrier to prevent release therethrough of an active ingredientcontained in the underlying core or first coating. In such embodiments,active ingredient is typically released from a portion of the dosageform which is not covered by the barrier shell portion. Such embodimentsadvantageously allow for further control of the surface area for releaseof the active ingredient. In certain such embodiments, the barrier shellportion preferably comprises a water insoluble material such as forexample a water insoluble polymer.

In certain other embodiments, one or more shell portions function as adelayed release coating to delay release of an active ingredient whichis contained in the core or a portion thereof. In these embodiments, thelag-time for onset of active ingredient release may be governed byerosion of the coating or diffusion through the coating or a combinationthereof. In certain such embodiments, the eroding matrix shell portionpreferably comprises a swellable erodible hydrophilic material.

In embodiments in which the first coating, the shell, or a portionthereof function to modify the release of an active ingredient which iscontained in the core or the subject coating or shell portion, thethickness of the coating or shell portion is critical to the releaseproperties of the dosage form. Advantageously the dosage forms of theinvention can be made with precise control over coating and shellthickness. In a preferred embodiment in which the first coating or shellportions function to modify the release of an active ingredient which iscontained in the core or the subject coating or shell portion, the firstcoating or shell portion or portions are made by the thermal cycle orthermal setting molding methods described herein.

Suitable thermal-reversible carriers for making the core, or the firstcoating, or the shell, or a portion thereof, by molding arethermoplastic materials typically having a melting point below about110° C., more preferably between about 20 and about 100° C. Examples ofsuitable thermal-reversible carriers for solvent-free molding includethermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides,low melting hydrophobic materials, thermoplastic polymers, thermoplasticstarches, and the like. Preferred thermal-reversible carriers includepolyethylene glycol and polyethylene oxide. Suitable thermoplasticpolyalkylene glycols for use as thermal-reversible carriers includepolyethylene glycol having molecular weight from about 100 to about20,000, e.g. from about 1000 to about 8,000 Daltons. Suitablethermoplastic polyalkalene oxides include polyethylene oxide having amolecular weight from about 100,000 to about 900,000 Daltons. Suitablelow-melting hydrophobic materials for use as thermal-reversible carriersinclude fats, fatty acid esters, phospholipids, and waxes which aresolid at room temperature, fat-containing mixtures such as chocolate;and the like. Examples of suitable fats include hydrogenated vegetableoils such as for example cocoa butter, hydrogenated palm kernel oil,hydrogenated cottonseed oil, hydrogenated sunflower oil, andhydrogenated soybean oil; and free fatty acids and their salts. Examplesof suitable fatty acid esters include sucrose fatty acid esters, mono,di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides. Examples of suitable phospholipidsinclude phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, and phosphotidic acid. Examples of suitable waxes which aresolid at room temperature include carnauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax.Suitable thermoplastic polymers for use as thermal-reversible carriersinclude thermoplastic water swellable cellulose derivatives,thermoplastic water insoluble polymers, thermoplastic vinyl polymers,thermoplastic starches, and thermoplastic resins, and combinationsthereof. Suitable thermoplastic water swellable cellulose derivativesinclude include hydroxypropylmethyl cellulose (HPMC), methyl cellulose(MC), carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose,hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC),hydroxyethylcellulose (HEC), hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts,derivatives, copolymers, and combinations thereof. Suitablethermoplastic water insoluble polymers include ethylcellulose, polyvinylalcohols, polyvinyl acetate, polycaprolactones, cellulose acetate andits derivatives, acrylates, methacrylates, acrylic acid copolymers, andthe like and derivatives, copolymers, and combinations thereof. Suitablethermoplastic vinyl polymers include polyvinylacetate, polyvinylalcohol, and polyvinyl pyrrolidone (PVP). Examples of suitablethermoplastic starches for use as thermal-reversible carriers includethose disclosed in U.S. Pat. No. 5,427,614, which is incorporated hereinby reference. Examples of suitable thermoplastic resins for use asthermal-reversible carriers include dammars, mastic, rosin, shellac,sandarac, and glycerol ester of rosin. In one embodiment, thethermal-reversible carrier for making the core, or a portion thereof, bymolding is selected from polyalkylene glycols, polyalkaline oxides, andcombinations thereof.

Suitable release-modifying excipients for making the core, or the shell,or a portion thereof, by solvent free or solvent based molding includebut are not limited to swellable erodible hydrophilic materials,pH-dependent polymers, pore formers, and insoluble edible materials. Inone embodiment, suitable release-modifying excipients for making thecore, or the shell, or a portion thereof, by molding includehydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylatecopolymer type B, and shellac, and combinations thereof.

Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or the shell, or aportion thereof by a solvent-free molding process include waterswellable cellulose derivatives, polyalkalene glycols, thermoplasticpolyalkalene oxides, acrylic polymers, hydrocolloids, clays, gellingstarches, and swelling cross-linked polymers, and derivitives,copolymers, and combinations thereof. Examples of suitable waterswellable cellulose derivatives include sodium carboxymethylcellulose,cross-inked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molceular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

Suitable pH-dependent polymers for use as release-modifying moldableexcipients for making the molded matrix or molded core or molded shellor a portion thereof by molding include enteric cellulose derivatives,for example hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate; naturalresins such as shellac and zein; enteric acetate derivatives such as forexample polyvinylacetate phthalate, cellulose acetate phthalate,acetaldehyde dimethylcellulose acetate; and enteric acrylate derivativessuch as for example polymethacrylate-based polymers such aspoly(methacrylic acid, methyl methacrylate) 1:2, which is commerciallyavailable from Rohm Pharma GmbH under the tradename EUDRAGIT S, andpoly(methacrylic acid, methyl methacrylate) 1:1, which is commerciallyavailable from Rohm Pharma GmbH under the tradename EUDRAGIT L; and thelike, and derivatives, salts, copolymers, and combinations thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients making the core, or the shell, or a portion thereof bymolding, include water-insoluble polymers, and low-melting hydrophobicmaterials. Examples of suitable water-insoluble polymers includeethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers; and the like and derivatives,copolymers, and combinations thereof. Suitable low-melting hydrophobicmaterials include fats, fatty acid esters, phospholipids, and waxes.Examples of suitable fats include hydrogenated vegetable oils such asfor example cocoa butter, hydrogenated palm kernel oil, hydrogenatedcottonseed oil, hydrogenated sunflower oil, and hydrogenated soybeanoil; and free fatty acids and their salts. Examples of suitable fattyacid esters include sucrose fatty acid esters, mono, di, andtriglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoylmacrogol-32 glycerides. Examples of suitable phospholipids includephosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, andphosphotidic acid. Examples of suitable waxes include carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate; andthe like.

Suitable pore formers for use as release-modifying excipients for makingthe molded matrix, the core, the shell, or a portion thereof by moldinginclude water-soluble organic and inorganic materials. In one embodimentthe pore former is hydroxypropylmethylcellulose. Examples of suitablewater-soluble organic materials include water soluble polymers includingwater soluble cellulose derivatives such ashydroxypropylmethylcellulose, and hydroxypropylcellulose; water solublecarbohydrates such as sugars, and starches; water soluble polymers suchas polyvinylpyrrolidone and polyethylene glycol, and insoluble swellingpolymers such as microcrystalline cellulose. Examples of suitable watersoluble inorganic materials include salts such as sodium chloride andpotassium chloride and the like and/or mixtures thereof.

The core may be in a variety of different shapes. For example, the coremay be shaped as a polyhedron, such as a cube, pyramid, prism, or thelike; or may have the geometry of a space figure with some non-flatfaces, such as a cone, truncated cone, cylinder, sphere, torus, or thelike. In certain embodiments the core may have the shape of a torus,cylinder, or truncated cone. In certain embodiments, the core has one ormore major faces. For example in embodiments wherein the core is acompressed tablet, the core surface typically has two opposing majorfaces formed by contact with the upper and lower punch faces in thecompression machine. In such embodiments the core surface typicallyfurther comprises a “belly-band” located between the two major faces,and formed by contact with the die walls in the compression machine.Exemplary core shapes which may be employed include tablet shapes formedfrom compression tooling shapes described by “The Elizabeth CompaniesTablet Design Training Manual” (Elizabeth Carbide Die Co., Inc., p. 7(McKeesport, Pa.) (incorporated herein by reference) as follows (thetablet shape corresponds inversely to the shape of the compressiontooling):

-   -   1. Shallow Concave.    -   2. Standard Concave.    -   3. Deep Concave.    -   4. Extra Deep Concave.    -   5. Modified Ball Concave.    -   6. Standard Concave Bisect.    -   7. Standard Concave Double Bisect.    -   8. Standard Concave European Bisect.    -   9. Standard Concave Partial Bisect.    -   10. Double Radius.    -   11. Bevel & Concave.    -   12. Flat Plain.    -   13. Flat-Faced-Beveled Edge (F.F.B.E.).    -   14. F.F.B.E. Bisect.    -   15. F.F.B.E. Double Bisect.    -   16. Ring.    -   17. Dimple.    -   18. Ellipse.    -   19. Oval.    -   20. Capsule.    -   21. Rectangle.    -   22. Square.    -   23. Triangle.    -   24. Hexagon.    -   25. Pentagon.    -   26. Octagon.    -   27. Diamond.    -   28. Arrowhead.    -   29. Bullet.    -   30. Shallow Concave.    -   31. Standard Concave.    -   32. Deep Concave.    -   33. Extra Deep Concave.    -   34. Modified Ball Concave.    -   35. Standard Concave Bisect.    -   36. Standard Concave Double Bisect.    -   37. Standard Concave European Bisect.    -   38. Standard Concave Partial Bisect.    -   39. Double Radius.    -   40. Bevel & Concave.    -   41. Flat Plain.    -   42. Flat-Faced-Beveled Edge (F.F.B.E.).    -   43. F.F.B.E. Bisect.    -   44. F.F.B.E. Double Bisect.    -   45. Ring.    -   46. Dimple.    -   47. Ellipse.    -   48. Oval.    -   49. Capsule.    -   50. Rectangle.    -   51. Square.    -   52. Triangle.    -   53. Hexagon.    -   54. Pentagon.    -   55. Octagon.    -   56. Diamond.    -   57. Arrowhead.    -   58. Bullet.    -   59. Barrel.    -   60. Half Moon.    -   61. Shield.    -   62. Heart.    -   63. Almond.    -   64. House/Home Plate.    -   65. Parallelogram.    -   66. Trapezoid.    -   67. FIG. 8/Bar Bell.    -   68. Bow Tie.    -   69. Uneven Triangle.

In one embodiment of the invention, the core comprises multipleportions, for example a first portion and a second portion. The portionsmay be prepared by the same or different methods and mated using varioustechniques, such as the thermal cycle molding and thermal settingmolding methods described herein. For example, the first and secondportions may both be made by compression, or both may be made bymolding. Or one portion may be made by compression and the other bymolding. The compression module of copending U.S. patent applicationSer. No. 09/966,509, pp. 16-27, the disclosure of which is incorporatedherein by reference, may be employed to make the compressed portion. Themolded portion may be made using the thermal cycle molding moduledescribed in U.S. patent application Ser. No. 09/966,497, pp. 27-51 orthe thermal setting molding module described in U.S. patent applicationSer. No. 09/966,450, pp. 57-63, the disclosures of which areincorporated herein by reference. A transfer device as described in U.S.patent application Ser. No. 09/966,414, pp. 51-57, the disclosure ofwhich is incorporated herein by reference, may be used to transfer thecompressed portion of the molding module.

The same or different active ingredient may be present in the first andsecond portions of the core. Alternately, one or more core portions maybe substantially free of active ingredients.

In embodiments wherein the shell is prepared by a solvent-free moldingprocess, the shell typically has a thickness of about 500 to about 4000microns. In embodiments wherein the shell or a portion thereof isprepared by a solvent-based molding process, the shell typically has athickness of less than about 800 microns, e.g. about 100 to about 600microns, e.g. about 150 to about 400 microns.

In certain other embodiments, the shell or a portion thereof is preparedby molding using a solvent based process. In such embodiments thesolvent-molded shell typically comprises at least about 10 weightpercent of a film-former. Here, the solvent-molded shell may optionallyfurther comprise up to about 55 weight percent of a release-modifyingagent. The solvent-molded shell may again also optionally furthercomprise up to about 30 weight percent total of various plasticizers,adjuvants and excipients.

In embodiments in which the shell is prepared by molding, either by asolvent-free process or by a solvent-based process, the shell typicallyis substantially free of pores in the diameter range of 0.5 to 5.0microns, i.e. has a pore volume in the pore diameter range of 0.5 to 5.0microns of less than about 0.02 cc/g, preferably less than about 0.01cc/g, more preferably less than about 0.005 cc/g. Typical compressedmaterials have pore volumes in this diameter range of more than about0.02 cc/g. Pore volume, pore diameter and density may be determinedusing a Quantachrome Instruments PoreMaster 60 mercury intrusionporosimeter and associated computer software program known as “Porowin.”The procedure is documented in the Quantachrome Instruments PoreMasterOperation Manual. The PoreMaster determines both pore volume and porediameter of a solid or powder by forced intrusion of a non-wettingliquid (mercury), which involves evacuation of the sample in a samplecell (penetrometer), filling the cell with mercury to surround thesample with mercury, applying pressure to the sample cell by: (i)compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil)pressure generator (up to 60000 psi maximum). Intruded volume ismeasured by a change in the capacitance as mercury moves from outsidethe sample into its pores under applied pressure. The corresponding poresize diameter (d) at which the intrusion takes place is calculateddirectly from the so-called “Washburn Equation”: d=−(4γ(cos θ)/P) whereγ is the surface tension of liquid mercury, θ is the contact anglebetween mercury and the sample surface and P is the applied pressure.

Equipment used for Pore Volume Measurements:

-   -   1. Quantachrome Instruments PoreMaster 60.    -   2. Analytical Balance capable of weighing to 0.0001 g.    -   3. Desiccator.

Reagents Used for Measurements:

-   -   1. High purity nitrogen.    -   2. Triply distilled mercury.    -   3. High pressure fluid (Dila AX, available from Shell Chemical        Co.).    -   4. Liquid nitrogen (for Hg vapor cold trap).    -   5. Isopropanol or methanol for cleaning sample cells.    -   6. Liquid detergent for cell cleaning.

Procedure:

The samples remain in sealed packages or as received in the dessicatoruntil analysis. The vacuum pump is switched on, the mercury vapor coldtrap is filled with liquid nitrogen, the compressed gas supply isregulated at 55 psi., and the instrument is turned on and allowed a warmup time of at least 30 minutes. The empty penetrometer cell is assembledas described in the instrument manual and its weight is recorded. Thecell is installed in the low pressure station and “evacuation and fillonly” is selected from the analysis menu, and the following settings areemployed:

-   -   Fine Evacuation time: 1 min.    -   Fine Evacuation rate: 10    -   Coarse Evacuation time: 5 min.

The cell (filled with mercury) is then removed and weighed. The cell isthen emptied into the mercury reservoir, and two tablets from eachsample are placed in the cell and the cell is reassembled. The weight ofthe cell and sample are then recorded. The cell is then installed in thelow-pressure station, the low-pressure option is selected from the menu,and the following parameters are set:

-   -   Mode: Low pressure    -   Fine evacuation rate: 10    -   Fine evacuation until: 200% Hg    -   Coarse evacuation time: 10 min.    -   Fill pressure: Contact+0.1    -   Maximum pressure: 50    -   Direction: Intrusion And Extrusion    -   Repeat: 0    -   Mercury contact angle: 140    -   Mercury surface tension: 480

Data acquisition is then begun. The pressure vs. cumulativevolume-intruded plot is displayed on the screen. After low-pressureanalysis is complete, the cell is removed from the low-pressure stationand reweighed. The space above the mercury is filled with hydraulic oil,and the cell is assembled and installed in the high-pressure cavity. Thefollowing settings are used:

-   -   Mode: Fixed rate    -   Motor speed: 5    -   Start pressure: 20    -   End pressure: 60,000    -   Direction: Intrusion and extrusion    -   Repeat: 0    -   Oil fill length: 5    -   Mercury contact angle: 140    -   Mercury surface tension: 480

Data acquisition is then begun and graphic plot pressure vs. intrudedvolume is displayed on the screen. After the high pressure run iscomplete, the low-and high-pressure data files of the same sample aremerged.

In embodiments in which the shell or a portion thereof comprises anactive ingredient intended to have immediate release from the dosageform, the shell or that portion thereof is preferably prepared via thesolvent-free molding method described above. In such embodiments thethermal-reversible carrier is preferably selected from polyethyleneglycol with weight average molecular weight from about 1450 to about20000, polyethylene oxide with weight average molecular weight fromabout 100,000 to about 900,000, and the like.

In embodiments in which the shell confers sustained, extended, orretarded release of an active ingredient contained in the shell, therelease-modifying agent in the shell preferably comprises a swellableerodible hydrophilic material, and may optionally comprise a secondarygelling agent such as for example cross-linked carboxymethylcellulose,cross-linked polyvinylpyrrolidone, or sodium starch glycolate.

In a particular embodiment of this invention at least one activeingredient contained within the dosage form exhibits a delayed andsustained release profile. By “delayed then sustained release profile”it is meant that the release of that particular active ingredient fromthe dosage form is delayed for a pre-determined time after ingestion bythe patient, and the delay period (“lag time”) is followed by sustained(prolonged, extended, or retarded) release of that active ingredient. Inthis embodiment, the shell or shell portion provides for the delayperiod, and is preferably substantially free of the active ingredient tobe released in a delayed then sustained manner. In such embodiments, thedelayed then sustained release active ingredient is preferably containedwithin the corresponding underlying core portion, or optionallydispersed throughout the entire core. In such embodiments the core orcore portion may function for example as an eroding matrix or adiffusional matrix, or an osmotic pump. In embodiments in which the coreportion functions as a diffusional matrix through which activeingredient is liberated in a sustained, extended, prolonged, or retardedmanner, the core portion preferably comprises a release-modifyingexcipient selected from combinations of insoluble edible materials andpore-formers. Alternately, in such embodiments in which the core portionis prepared by molding, the thermal-reversible carrier may function bydissolving and forming pores or channels through which the activeingredient may be liberated. In embodiments in which the core portionfunctions as an eroding matrix from which dispersed active ingredient isliberated in a sustained, extended, prolonged, or retarded manner, thecore portion preferably comprises a release-modifying compressible ormoldable excipient selected from swellable erodible hydrophilicmaterials, pH-dependent polymers, and combinations thereof.

In another particular embodiment of this invention at least one activeingredient contained within the dosage form exhibits a double pulserelease profile. By “double pulse” it is meant that a first portion ofactive ingredient is released essentially immediately upon contacting ofthe dosage form with a liquid medium, followed by a delay period,followed by immediate release of a second portion of active ingredient.In such embodiments in which one or more shell portions contain activeingredient which is released essentially immediately upon ingestion ofthe dosage form, the shell portion preferably comprises materials whichexhibit rapid dissolution in gastro-intestinal fluids. For example theimmediate release shell portion or portions may comprise readily solublematerials selected from water soluble or water swellable thermoplasticfilm formers, water soluble or water swellable thickeners,crystallizable and non-crystallizable carbohydrates. In certain suchembodiments, suitable water soluble or water swellable thermoplasticfilm formers may be selected from water swellable cellulose derivatives,thermoplastic starches, polyalkalene glycols, polyalkalene oxides, andamorphous sugar glass, and combinations thereof. In certain other suchembodiments, suitable film formers may be selected from film formingwater soluble polymers such as for example water soluble vinyl polymers,water soluble polycarbohydrates, water swellable cellulose derivatives,and water soluble copolymers; film-forming proteins, and combinationsthereof. In certain other such embodiments, suitable thickeners may beselected from gelling polymers or hydrocolloids; gelling starches, andcrystallizable carbohydrates. In certain other such embodiments,suitable non-crystallizable carbohydrates may be selected frompolydextrose, starch hydrolysates, and non-crystallizable sugaralcohols. In such embodiments, the immediate release shell portion willpreferably be breached or dissolved within 30 minutes in 900 ml water or0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USPtype 2 (Paddle method) at 50 or 100 rpm.

This invention will be illustrated by the following examples, which arenot meant to limit the invention in any way.

EXAMPLE 1

Dosage forms according to the invention were made as follows. First,cores were prepared using the following ingredients:

Mg/ Trade Weight Dosage Granulation Name Manufacturer % FormPseudoephedrine BASF 15.0 85 HCl Crystal PharmaChemikalien GmbH & Co.Ludwigshafen/ Rhein. Polyethylene Polyox ® Union Carbide 75.0 424 OxideWSR N-750 Corporation, (MW 300,000) Danbury, CT Hydroxypropyl MethocelThe Dow Chemical 8.5 48 Methylcellulose E5 Company, Midland, MIMagnesium Mallinckrodt Inc., 1.5 9 Stearate St. Louis, MO FD&C Blue #1Colorcon Inc., Trace West Point, PA Amount Alcohol USP (dried assolvent)

The pseudoephedrine HCl crystal, hydroxypropyl methylcellulose,polyethylene oxide and FD&C Blue #1 were mixed in a plastic bag for 1-2minutes. This powder mixture was added to the (5 qt) bowl of a planetarymixer (Hobart Corp., Dayton, Ohio). The alcohol was added to the powdermixture while mixing at low speed. The ingredients were mixed for 10minutes. The resulting granulation was removed from the bowl and wasdried at room temperature for 12 to 16 hours to remove all residualsolvent. The granulation was screened through a 20-mesh screen and putinto a plastic bag. Magnesium stearate was added to the dry granules,followed by mixing for 3 minutes.

Cores were then prepared by pressing the granulation using a ManestyBeta-press (Thomas Engineering, Inc., Hoffman Estates, Ill.). A round,concave punch and die unit having 0.4455″ diameter was used forcompression. Granulation was fed into the cavity of the press andcompressed into solid cores.

A first coating material was next prepared from the followingingredients:

Mg/ Weight dosage Granulation Trade Name Manufacturer % FormtPolycaprolactones CAPA 686 Solvay Interox, Inc., 100 286 IsopropanolLaporte, TX (dried as solvent)

The polycaprolactones were first added to a beaker. The isopropanol wasadded thereto and the combination was mixed with a spatula until auniform dispersion was obtained.

A thermal cycle molding module as described in copending U.S.application Ser. No. 09/966,497 at pages 27-51, the disclosure of whichis incorporated herein by reference, was used to apply the first coatingmaterial onto the cores. The thermal cycle molding module was alaboratory scale unit and comprised a single mold made from an uppermold assembly and a lower mold assembly. The lower mold assembly wasfirst cycled to a cold stage at 25° C. for 30 seconds. First coatingmaterial was then introduced into a cavity in the lower mold assembly. Acore as prepared above was then inserted into the same cavity. The uppermold assembly was then cycled to a cold stage at 25° C. for 30 seconds.First coating material was added to a cavity in the upper mold assembly.The lower and upper mold assemblies were mated and cycled to a hot stageat 85° C. for 1 minute, followed by cycling to a cold stage at 10° C.for 1 minute to harden the first coating. The upper and lower moldassemblies were separated and the core coated with the first coating wasejected.

The “weight gains” of the cores due to the presence of the first coatingwere recorded. The coated cores were dried at room temperature for 24hours to remove all residual solvent.

Next, holes were drilled through the centers of the coated cores. 0.277cm holes were drilled through in one set of coated cores using a ⅜″drill (model 315.10491, Sears, Roebuck and Co.) equipped with a 7/64″drill bit. 0.397-cm holes were drilled in a second set of coated coresusing a ⅜″ drill equipped with a 5/32″ drill bit.

Finally, a shell material was prepared using the following ingredient:

Mg/Dosage Shell Trade Name Manufacturer Weight % Form PolyethyleneCarbowax ® Union Carbide 100 2042 Glycol 3350 Corporation, Danbury, CT

A beaker was submersed in a 70° C. water bath (Ret digi-visc;Antal-Direct, Wayne, Pa.). The polyethylene glycol (PEG) was added tothe beaker and was mixed with a spatula until melted. The molten PEG wasthen introduced into a rubber capsule-shape mold (20.5 mm×12.6 mm×10.7mm). A coated core containing a hole, prepared as described above, wasinserted into the mold. Additional molten PEG was added to fill themold. The mold was then allowed to cool for five minutes, hardening thePEG into a shell. The resulting dosage form comprising a PEG shell wasremoved from the mold.

The release profiles versus time for two dosage forms of the inventionwere compared with the release profile of an uncoated solid corematerial. The release profile (i.e. % released vs. time) for each isshown in FIG. 6. In FIG. 6, curve “c” is the release profile of theuncoated solid core, curve “b” is the release profile of the dosage formhaving a 0.397 cm hole, and curve “a” is the release profile of thedosage form having a 0.280 cm hole.

EXAMPLE 2

Dosage forms of the invention are made in a continuous process using anapparatus comprising three thermal cycle molding modules linked inseries via two transfer devices as described at pages 14-16 of copendingU.S. application Ser. No. 09/966,939, the disclosure of which isincorporated herein by reference. The dosage forms have the structureshown in FIG. 7 and each comprise a core having a toroidal shape (i.e.,donut-shaped) coated first with an first coating on its entire exteriorsurface except for the surface inside the hole of the donut. The dosageforms further comprise a shell completely overlying the core and thefirst coating, thereby forming the outermost layer of the dosage form.

The core is made of a core flowable material comprising the followingingredients:

Trade Weight Mg/ Tablet Name Manufacturer % Tablet PolyethyleneCarbowax ® Union Carbide 42.0 238 Glycol 3350 Corporation, Danbury, CTShellac Powder Regular Mantrose-Haeuser 10.0 56 bleached Company,Atteboro, shellac MA Croscarmellose Ac-Di-Sol ® FMC Corporation, 21.0119 Sodium Newark, DE Pseudoephedrine BASF 27.0 153 HydrochloridePharmaChemikalien Crystal GmbH & Co., Ludwigshafen/ Rhein.

The ingredients are processed as set forth in Example 1.

The first coating is made from an first coating flowable materialcomprising the following ingredients:

Weight Mg/dosage Granulation Trade Name Manufacturer % FormtPolycaprolactones CAPA 686 Solvay 100 286 Isopropanol Interox, Inc.,(dried as solvent) Laporte, TX

The polycaprolactones are first mixed with the isopropanol until auniform dispersion is obtained.

The shell is made from a shell flowable material comprising thefollowing ingredient:

Mg/Dosage Shell Trade Name Manufacturer Weight % Form PolyethyleneCarbowax ® Union Carbide 100 2042 Glycol 3350 Corporation, Danbury, CT

The thermal cycle molding modules have the general configuration shownin FIG. 3 of copending U.S. application Ser. No. 09/966,939, whichdepicts a thermal cycle molding module 200 comprising a rotor 202 aroundwhich a plurality of mold units 204 are disposed. Each thermal cyclemolding module includes its own reservoir 206 (see FIG. 4 of copendingU.S. application Ser. No. 09/966,939) for holding the core flowablematerial, the first coating flowable material, and the shell flowablematerial, respectively. In addition, each thermal cycle molding moduleis provided with a temperature control system for rapidly heating andcooling the mold units. FIGS. 55 and 56 of copending U.S. applicationSer. No. 09/966,939 depict the temperature control system 600.

The cores are made in a first thermal cycle molding module, which islinked via a first transfer device to a second thermal cycle moldingmodule, which is in turn linked via a second transfer device to a thirdthermal cycle molding module. The first thermal cycle molding module hasthe specific configuration shown in FIG. 26A of copending U.S.application Ser. No. 09/966,939. The first thermal cycle molding modulecomprises center mold assemblies 212 and upper mold assemblies 214 asshown in FIG. 26C, which mate to form mold cavities having the shape ofa donut. As rotor 202 rotates, the opposing center and upper moldassemblies close. Core flowable material, which is heated to a flowablestate in reservoir 206, is injected into the resulting mold cavities.The temperature of the core flowable material is then decreased,hardening the core flowable material into donut-shaped cores. The moldassemblies open and eject the cores, which are received by the firsttransfer device.

Both the first and second transfer devices have the structure shown as300 in FIG. 3 of copending U.S. application Ser. No. 09/966,939. Eachcomprises a plurality of transfer units 304 attached in cantileverfashion to a belt 312 as shown in FIGS. 68 and 69 of copending U.S.application Ser. No. 09/966,939. The transfer devices rotate and operatein sync with the thermal cycle molding modules to which they arecoupled. Transfer units 304 comprise retainers 330 for holding thepartially made dosage forms as they travel around each transfer device.

The first transfer device transfers the donut-shaped cores to the secondthermal cycle molding module, which applies the first coating to thecores. The second thermal cycle molding module is of the type shown inFIG. 28A of copending U.S. application Ser. No. 09/966,939. The moldunits 204 of the second thermal cycle molding module comprise upper moldassemblies 214, rotatable center mold assemblies 212 and lower moldassemblies 210 as shown in FIG. 28C. Donut-shaped cores are continuouslytransferred to the mold assemblies, which then close over the cores.First coating flowable material, which is heated to a flowable state inreservoir 206, is injected into the mold cavities created by the closedmold assemblies. The temperature of the first coating flowable materialis then decreased, hardening it. The mold assemblies open and eject thepartially coated cores, which are received by the second transferdevice. Coating is performed in two steps, each half of the cores beingcoated separately as shown in the flow diagram of FIG. 28B of copendingU.S. application Ser. No. 09/966,939 via rotation of the center moldassembly.

The construction of the mold assemblies in the second thermal cyclemolding module is such that the portion of the donut-shaped cores insidethe hole is masked by the mold assemblies during application of thefirst coating.

The inside surface of the mold assembly has a masking protrusion tocover the hole of the donut-shaped cores. Accordingly, the surface ofthe cores inside the hole remains uncoated upon exiting the secondthermal cycle molding module.

The second transfer device carries the partially coated cores to thethird thermal cycle molding module, which applies the shell. The thirdthermal cycle molding module is also of the type shown in FIGS. 28A-C ofcopending U.S. application Ser. No. 09/966,939 comprising rotatablecenter mold assemblies 212, lower mold assemblies 210 and upper moldassemblies 214. Cores bearing the first coating are continuouslytransferred to the mold assemblies of the third thermal cycle moldingmodule. Shell flowable material, which is heated to a flowable state inreservoir 206, is injected into the mold cavities created by the closedmold assemblies holding the cores. The temperature of the shell flowablematerial is then decreased, hardening it. The mold assemblies open andeject the finished dosage forms. Shell coating is performed in twosteps, each half of the dosage forms being coated separately as shown inthe flow diagram of FIG. 28B of copending U.S. application Ser. No.09/966,939 via rotation of the center mold assembly.

Although this invention has been illustrated by reference to specificembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications may be made which clearly fall withinthe scope of this invention.

The invention claimed is:
 1. A dosage form comprising: (a) at least oneactive ingredient: (b) a core having a first surface portion upon whichresides a first coating and a second surface portion which issubstantially free of the first coating; and (c) a shell which residesupon at least part of both the first coating and the second surfaceportion of the core, wherein the shell comprises a different materialfrom the first coating, wherein the core comprises a cavity, wherein thecavity is an aperture which extends entirely through the core, whereinat least a portion of the second surface portion of the core is locatedwithin the cavity, and wherein the shell resides upon at least a part ofthe second surface portion of the core which is located within thecavity.
 2. The dosage form of claim 1, in which the shell resides overall the first coating and the second surface of the core.
 3. The dosageform of claim 1, in which the shell comprises a material selected fromwater soluble or water swellable thermoplastic film formers, watersoluble or water swellable thickeners, crystallizable andnon-crystallizable carbohydrates.
 4. The dosage form of claim 1, inwhich the shell comprises a thermal-reversible carrier selected from thegroup consisting of thermoplastic polyalkylene glycols, thermoplasticpolyalkylene oxides, and combinations thereof.
 5. A dosage formcomprising: (a) at least one active ingredient; (b) a core comprising acenter portion having an exterior surface and an annular portion havingan exterior surface and an interior surface, wherein the annular portioninterior surface is in contact with at least a portion of the centerportion exterior surface, and a first coating resides on at least aportion of the annular portion exterior surface, and in which the coreannular portion has the shape of a torus; and (c) a shell which residesupon at least a portion of the exterior surface of the center portion,wherein the shell comprises a different material than the first coating.6. The dosage form of claim 1, in which the core comprises at least oneactive ingredient.
 7. The dosage form of claim 5, in which the centerportion of the core comprises at least one active ingredient.
 8. Thedosage form of claim 5, in which the annular portion of the corecomprises at least one active ingredient.
 9. The dosage form of claim 5,in which the center portion of the core comprises a first activeingredient and the annular portion of the core comprises a second activeingredient.
 10. The dosage form of claim 1, in which the shell comprisesat least one active ingredient.
 11. The dosage form of claim 1, in whichboth the shell and the core each comprise at least one activeingredient.
 12. The dosage form of claim 5, in which the first coatingresides upon the entire annular portion exterior surface.
 13. The dosageform of claim 12, in which the shell resides upon the entire firstcoating and the center portion surface.
 14. The dosage form of claim 5,which the shell comprises a material selected from water soluble orwater swellable thermoplastic film formers, water soluble or waterswellable thickeners, crystallizable and non-crystallizablecarbohydrates.
 15. The dosage form of claim 5, in which the shellcomprises a thermal-reversible carrier selected from the groupconsisting of thermoplastic polyalkylene glycols, thermoplasticpolyalkylene oxides, and combinations thereof.
 16. A dosage formcomprising: (a) at least one active ingredient; (b) a core having anouter surface and a cavity which extends through the core having theshape of a torus such that the core outer surface has at least a firstopening therein; (c) a first coating which resides on at least a portionof the core outer surface, wherein the first shell portion comprises adifferent material from the first coating; and (d) a first shell portionwhich is adjacent to the first opening and covers at least the firstopening.
 17. The dosage form of claim 16, in which the cavity extendsentirely through the core such that the core has first and secondopenings therein, the first shell portion is adjacent to and covers atleast the first opening, and the dosage form additionally comprises asecond shell portion which is adjacent to and covers at least the secondopening, wherein the first and second shell portions each comprise amaterial different from the first coating.
 18. The dosage form of claim16, in which the first shell portion comprises at least one watersoluble material.
 19. The dosage form of claim 16, in which the secondshell portion comprises at least one water soluble material.
 20. Thedosage form of claim 16, in which the first and second shell portionseach comprise at least one water soluble material.
 21. The dosage formof claim 16, in which the first shell portion or the core or acombination thereof comprises at least one active ingredient.
 22. Thedosage form of claim 16, in which the first shell portion, second shellportion or the core or a combination thereof comprises at least oneactive ingredient.
 23. The dosage form of claim 16, in which the firstshell portion resides upon at least a portion of the first coating. 24.The dosage form of claim 22, in which the shell resides upon the entireouter surface of the first coating.
 25. The dosage form of claim 1, inwhich at least a portion of the active ingredient is released in asustained manner.
 26. The dosage form of claim 24, in which the dosageform releases at least a portion of the active ingredient at asubstantially constant rate.
 27. The dosage form of claim 5, in whichthe center portion of the core provides a time delay to the release ofactive ingredient from the annular portion of the core.
 28. The dosageform of claim 1, in which the core functions as an eroding matrix. 29.The dosage form of claim 1, in which the core functions as a diffusionalmatrix for the release of active ingredient contained therein.
 30. Thedosage form of claim 1, in which the core comprises a release-modifyingexcipient selected from the group consisting of swellable erodiblehydrophilic materials, insoluble edible materials, pH-dependentpolymers, and mixtures thereof.
 31. The dosage form of claim 1, in whichthe first coating comprises at least about 30 weight percent of athermal reversible carrier, based on the weight of the first coating.32. The dosage form of claim 1, in which the first coating comprises atlease about 10 weight percent of a film former selected from the groupconsisting of film-forming water soluble polymers, film-formingproteins, film-forming water insoluble polymers, and film-formingpH-dependent polymers, and combinations thereof.
 33. The dosage form ofclaim 1, in which the shell or shell portion comprises thermoplasticpolyalkylene glycols, thermoplastic polyalkylene oxides, andcombinations thereof.
 34. The dosage form of claim 1, in which the shellportion is breached or dissolved within 30 minutes in 900 ml water or0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USPtype 2 (Paddle method) at 50 or 100 rpm.
 35. The dosage form of claim 1,in which the release of at least one active ingredient follows a doublepulse profile.
 36. The dosage form of claim 1, in which the release ofat least one active ingredient follows a delayed then sustained releaseprofile.
 37. The dosage form of claim 1, in which the release of one ormore active ingredients follows a zero-order, first-order, or squareroot of time profile.
 38. The dosage form of claim 1, in which the shellis substantially free of pores in the diameter range of 0.5 to 5.0microns.
 39. The dosage form of claim 1, in which the first coatingcomprises up to about 55 weight percent of a release-modifying excipientselected from water-insoluble polymers and low-melting hydrophobicmaterials and combinations thereof.
 40. The dosage form of claim 39, inwhich the release-modifying excipient is a polycaprolactone.